Potassium Carbonate → 5-amino-N-(5-(4-aminoazepan-1-yl)-1-ethyl-1H-pyrazol-4-yl)-2-(2,6-difluorophenyl)thiazole-4-carboxamide

HRID 2089359Notes

Reaction equation

HRID 2089359 reaction equation
[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[S:10][C:11]([NH:38]C(=O)OC(C)(C)C)=[C:12]([C:14](=[O:37])[NH:15][C:16]2[CH:17]=[N:18][N:19]([CH2:35][CH3:36])[C:20]=2[N:21]2[CH2:27][CH2:26][CH2:25][CH:24]([NH:28]C(=O)C(F)(F)F)[CH2:23][CH2:22]2)[N:13]=1.C([O-])([O-])=O.[K+].[K+]>Cl.O1CCOCC1>[NH2:38][C:11]1[S:10][C:9]([C:3]2[C:4]([F:8])=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])=[N:13][C:12]=1[C:14]([NH:15][C:16]1[CH:17]=[N:18][N:19]([CH2:35][CH3:36])[C:20]=1[N:21]1[CH2:27][CH2:26][CH2:25][CH:24]([NH2:28])[CH2:23][CH2:22]1)=[O:37]

Participants

5

Reactant 2

HCID 11430Potassium CarbonateHCID 86658424tert-butyl 2-(2,6-difluorophenyl)-4-(1-ethyl-5-(4-(2,2,2-trifluoroacetamido)azepan-1-yl)-1H-pyrazol-4-ylcarbamoyl)thiazol-5-ylcarbamate

Product 1

HCID 584648525-amino-N-(5-(4-aminoazepan-1-yl)-1-ethyl-1H-pyrazol-4-yl)-2-(2,6-difluorophenyl)thiazole-4-carboxamideYield 99%

Reagents, catalysts & solvents 2

HCID 313Hydrochloric AcidSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
60 °C

Procedure

A solution of tert-butyl 2-(2,6-difluorophenyl)-4-(1-ethyl-5-(4-(2,2,2-trifluoroacetamido)azepan-1-yl)-1H-pyrazol-4-ylcarbamoyl)thiazol-5-ylcarbamate (0.17 g, 0.26 mmol) in HCl in 1,4-dioxane (4 M, 5 mL) was allowed to stand at room temperature for 40 hr. The reaction mixture was concentrated under reduced pressure and the residue dissolved in 50% aqueous MeOH (20 mL). K2CO3 (1.22 g, 8.84 mmol) was added and the mixture heated at 60° C. for 3 hr. The mixture was allowed to cool, concentrated to approximately 5 mL and extracted with DCM. The combined organic layers were passed through a phase separation cartridge and the solvent removed under reduced pressure. Purification of the residue by passing through an SCX column washing with DCM and MeOH and eluting with 1 N ammonia in MeOH gave 241 as a cream solid (118 mg, 99%). 1H-NMR (400 MHz, CDCl3) δ 8.67 (s, 1H), 7.92 (s, 1H), 7.36-7.28 (m, 1H), 7.06-6.97 (m, 2H), 6.14 (s, 2H), 4.05 (q, J=7 Hz, 2H), 3.29-3.12 (m, 5H), 2.02-1.88 (m, 3H), 1.75-1.60 (m, 3H), 1.43 (t, J=7 Hz, 3H). RNH2 not seen. LCMS (ES+) m/z 462.0 (M+1).

Workup

  1. concentrationThe reaction mixture was concentrated under reduced pressure
  2. dissolutionthe residue dissolved in 50% aqueous MeOH (20 mL)
  3. temperatureto cool
  4. concentrationconcentrated to approximately 5 mL
  5. extractionextracted with DCM
  6. customThe combined organic layers were passed through a phase separation cartridge
  7. customthe solvent removed under reduced pressure
  8. customPurification of the residue
  9. washwashing with DCM and MeOH
  10. washeluting with 1 N ammonia in MeOH

Sources & evidence

ORD record
ord-e23b7392695f4218b8b4c3b7e111b58b
Source dataset
uspto-grants-2013_05
Patent number
US08436001B2

Reaction notes

Loading…